Chronic myelogenous leukaemia (CML) is a hematological stem cell disorder that is associated with a specific chromosomal abnormality whereby the Abelson (c-abl) proto-oncogene, translocated from chromosome 9, is fused to the breakpoint cluster region (bcr) gene on chromosome 22 as shown in slide 2. The bcr-abl fusion gene codes for a tyrosine kinase that is activated constitutively and is thus able to transform cells and cause malignancy: white blood cells divide constantly leading to a blast crisis. Recently, a selective inhibitor of p210-Bcr-Abl tyrosine kinase, STI-571, was designed by Druker and co-workers. See Drucker, et al., Nature Med., 2, 561-566 (1996) and Schindler, et al., Science, 289, 1938-1941 (2000). STI-571 (tradename: Gleevec®) is the first kinase inhibitor approved by the FDA and blocks the ATP-binding site on Abl and Bcr-Abl kinases, resulting in both inhibition of proliferation and induction of apoptosis in Bcr-Abl positive cell lines. While STI-571 leads to a complete hematological response in 96% of the patients treated for more than four weeks, patients with advanced disease often relapse, their tumor cells become resistant to the drug and these eventually grow out of control. One of the possible causes of resistance of cancerous cells to STI-571 is a mutation that replaces a single amino acid in the active site of the kinase, preventing binding of the drug to the kinase. See Gorre, et al., Science, 293, 876-880 (2001).

The present invention relates to the goal of preparing novel tyrosine kinase inhibitors that would be given alone or in combination with STI-571 to cancer patients since the cancerous cells should be less able to become resistant to all the drugs at once. In addition, novel active substances that would hit alternative targets and work alone or in synergy with STI-571 are also sought after targets.